rs8076337

Positions:

• chr17-74301041-A-G
• chr17-74301041-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_023036.6(DNAI2):​c.865-5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,613,340 control chromosomes in the GnomAD database, including 119,963 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8703 hom., cov: 31)
  • Exomes 𝑓: 0.39 (111260 hom.)
• Consequence: DNAI2 NM_023036.6 splice_region, intron
• Scores: Splicing: ADA: 0.00001633
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -4.37

Genes affected

DNAI2 (HGNC:18744): (dynein axonemal intermediate chain 2) The protein encoded by this gene belongs to the dynein intermediate chain family, and is part of the dynein complex of respiratory cilia and sperm flagella. Mutations in this gene are associated with primary ciliary dyskinesia type 9. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-74301041-A-G is Benign according to our data. Variant chr17-74301041-A-G is described in ClinVar as [Benign]. Clinvar id is 178764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-74301041-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAI2	NM_023036.6	c.865-5A>G		splice_region_variant, intron_variant		ENST00000311014.11	NP_075462.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAI2	ENST00000311014.11	c.865-5A>G		splice_region_variant, intron_variant		1	NM_023036.6	ENSP00000308312.6

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49916 AN: 151894 Hom.: 8697 Cov.: 31

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.334

GnomAD3 exomes AF: 0.344 AC: 86386 AN: 251328 Hom.: 15652 AF XY: 0.352 AC XY: 47810 AN XY: 135842

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.205

Gnomad SAS exome AF: 0.343

Gnomad FIN exome AF: 0.349

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.372

GnomAD4 exome AF: 0.385 AC: 562691 AN: 1461328 Hom.: 111260 Cov.: 58 AF XY: 0.385 AC XY: 279709 AN XY: 726952

Gnomad4 AFR exome AF: 0.213

Gnomad4 AMR exome AF: 0.261

Gnomad4 ASJ exome AF: 0.372

Gnomad4 EAS exome AF: 0.178

Gnomad4 SAS exome AF: 0.344

Gnomad4 FIN exome AF: 0.351

Gnomad4 NFE exome AF: 0.409

Gnomad4 OTH exome AF: 0.364

GnomAD4 genome AF: 0.328 AC: 49923 AN: 152012 Hom.: 8703 Cov.: 31 AF XY: 0.323 AC XY: 23974 AN XY: 74304

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.373

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.330

Gnomad4 FIN AF: 0.333

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.331

Alfa AF: 0.382 Hom.: 5230

Bravo AF: 0.321

Asia WGS AF: 0.242 AC: 842 AN: 3478

EpiCase AF: 0.405

EpiControl AF: 0.414

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 11, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	865-5A>G in intron 7 of DNAI2: This variant is not expected to have clinical sig nificance because it has been identified in 41.0% (3527/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs8076337). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia 9 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.054
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs8076337; hg19: chr17-72297180; COSMIC: COSV56758575;